Is RAG2 p.Pro377Ser (c.1129C>T) pathogenic?

RAG2 p.Pro377Ser (c.1129C>T) is classified Uncertain significance in RAG2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.2191); Very rare (popmax 8.47e-05%, nfe); Associated with Omenn syndrome.

What condition is associated with RAG2 p.Pro377Ser (c.1129C>T)?

RAG2 p.Pro377Ser (c.1129C>T) is associated with Omenn syndrome (ClinVar).

How common is RAG2 p.Pro377Ser (c.1129C>T) in the general population?

RAG2 p.Pro377Ser (c.1129C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Omenn syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RAG2 p.Pro377Ser (c.1129C>T)?

AlphaMissense predicts likely benign (score 0.2191) — an in-silico prediction, not a clinical call.

RAG2 p.Pro377Ser

c.1129C>T · VCV4060677

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Omenn syndrome

Computational evidence

Protein change
AlphaMissense	0.2191	likely benign
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -3.79	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 1/1,461,850 · genomes 0/152,258 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RAG2
Protein: p.Pro377Ser
Coding: c.1129C>T
MANE Select: NM_000536
Type: single nucleotide variant
Location: chr11:36593040 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB
Residue 377: the 'disordered' region

Full RAG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Omenn syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Omenn syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RAG2 p.Pro377Leu Uncertain significance ★ ⚠ same residue
RAG2 p.Pro377= Likely benign ★ same residue
RAG2 p.Arg229Gln Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg229Trp Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg39Gly Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg73Cys Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Asp65Tyr Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Glu437Lys Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rag2-p-pro377ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown